title: Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model.
abstract: Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging.
authors.affiliation: NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burn Institute, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: A Aria
authors.initials: AA
authors.lastname: Tzika
authors.forename: Cibely Cristine
authors.initials: CC
authors.lastname: Fontes-Oliveira
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shestov
authors.forename: Caterina
authors.initials: C
authors.lastname: Constantinou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.forename: Valeria
authors.initials: V
authors.lastname: Righi
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Mintzopoulos
authors.forename: Silvia
authors.initials: S
authors.lastname: Busquets
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Lopez-Soriano
authors.forename: Sylvain
authors.initials: S
authors.lastname: Milot
authors.forename: Francois
authors.initials: F
authors.lastname: Lepine
authors.forename: Michael N
authors.initials: MN
authors.lastname: Mindrinos
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
authors.forename: Josep M
authors.initials: JM
authors.lastname: Argiles
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D002100:Cachexia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002952:Citric Acid Cycle; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009369:Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D000255:Adenosine Triphosphate